MK12_HUMAN
ID MK12_HUMAN Reviewed; 367 AA.
AC P53778; Q14260; Q6IC53; Q99588; Q99672;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1998, sequence version 3.
DT 03-AUG-2022, entry version 219.
DE RecName: Full=Mitogen-activated protein kinase 12;
DE Short=MAP kinase 12;
DE Short=MAPK 12;
DE EC=2.7.11.24 {ECO:0000269|PubMed:10212242};
DE AltName: Full=Extracellular signal-regulated kinase 6;
DE Short=ERK-6;
DE AltName: Full=Mitogen-activated protein kinase p38 gamma;
DE Short=MAP kinase p38 gamma;
DE AltName: Full=Stress-activated protein kinase 3;
GN Name=MAPK12; Synonyms=ERK6, SAPK3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF TYR-185.
RC TISSUE=Skeletal muscle;
RX PubMed=8633070; DOI=10.1073/pnas.93.9.4355;
RA Lechner C., Zahalka M.A., Giot J.-F., Moeller N.P.H., Ullrich A.;
RT "ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast
RT differentiation.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:4355-4359(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Skeletal muscle;
RX PubMed=9169156; DOI=10.1006/geno.1997.4633;
RA Goedert M., Hasegawa J., Craxton M., Leversha M.A., Clegg S.;
RT "Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to
RT chromosome 22q13.3 by fluorescence in situ hybridization.";
RL Genomics 41:501-502(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=8920915; DOI=10.1006/bbrc.1996.1662;
RA Li Z., Jiang Y., Ulevitch R.J., Han J.;
RT "The primary structure of p38 gamma: a new member of p38 group of MAP
RT kinases.";
RL Biochem. Biophys. Res. Commun. 228:334-340(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT MET-103.
RX PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA Beare D.M., Dunham I.;
RT "A genome annotation-driven approach to cloning the human ORFeome.";
RL Genome Biol. 5:R84.1-R84.11(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF ATF2; ELK1 AND MBP, AND ACTIVITY REGULATION.
RX PubMed=9430721; DOI=10.1074/jbc.273.3.1741;
RA Enslen H., Raingeaud J., Davis R.J.;
RT "Selective activation of p38 mitogen-activated protein (MAP) kinase
RT isoforms by the MAP kinase kinases MKK3 and MKK6.";
RL J. Biol. Chem. 273:1741-1748(1998).
RN [8]
RP INTERACTION WITH SNTA1, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
RP AND CATALYTIC ACTIVITY.
RX PubMed=10212242; DOI=10.1074/jbc.274.18.12626;
RA Hasegawa M., Cuenda A., Spillantini M.G., Thomas G.M., Buee-Scherrer V.,
RA Cohen P., Goedert M.;
RT "Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-
RT syntrophin. A mechanism for specific substrate recognition.";
RL J. Biol. Chem. 274:12626-12631(1999).
RN [9]
RP PHOSPHORYLATION BY MAP2K6/MKK6.
RX PubMed=11010976; DOI=10.1074/jbc.m007835200;
RA Alonso G., Ambrosino C., Jones M., Nebreda A.R.;
RT "Differential activation of p38 mitogen-activated protein kinase isoforms
RT depending on signal strength.";
RL J. Biol. Chem. 275:40641-40648(2000).
RN [10]
RP FUNCTION IN REGULATION OF THE G2 CHECKPOINT.
RX PubMed=10848581; DOI=10.1128/mcb.20.13.4543-4552.2000;
RA Wang X., McGowan C.H., Zhao M., He L., Downey J.S., Fearns C., Wang Y.,
RA Huang S., Han J.;
RT "Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell
RT cycle arrest.";
RL Mol. Cell. Biol. 20:4543-4552(2000).
RN [11]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Heart;
RX PubMed=11991731; DOI=10.1006/jmcc.2001.1523;
RA Court N.W., dos Remedios C.G., Cordell J., Bogoyevitch M.A.;
RT "Cardiac expression and subcellular localization of the p38 mitogen-
RT activated protein kinase member, stress-activated protein kinase-3
RT (SAPK3).";
RL J. Mol. Cell. Cardiol. 34:413-426(2002).
RN [12]
RP MUTAGENESIS, SUBCELLULAR LOCATION, AND INTERACTION WITH SH3BP5.
RX PubMed=12167088; DOI=10.1042/bj20020553;
RA Wiltshire C., Matsushita M., Tsukada S., Gillespie D.A., May G.H.;
RT "A new c-Jun N-terminal kinase (JNK)-interacting protein, Sab (SH3BP5),
RT associates with mitochondria.";
RL Biochem. J. 367:577-585(2002).
RN [13]
RP FUNCTION.
RX PubMed=14592936; DOI=10.1152/ajpregu.00563.2003;
RA Ho R.C., Alcazar O., Fujii N., Hirshman M.F., Goodyear L.J.;
RT "p38gamma MAPK regulation of glucose transporter expression and glucose
RT uptake in L6 myotubes and mouse skeletal muscle.";
RL Am. J. Physiol. 286:R342-R349(2004).
RN [14]
RP MUTAGENESIS OF ASP-179 AND PHE-330.
RX PubMed=15284239; DOI=10.1074/jbc.m404595200;
RA Diskin R., Askari N., Capone R., Engelberg D., Livnah O.;
RT "Active mutants of the human p38alpha mitogen-activated protein kinase.";
RL J. Biol. Chem. 279:47040-47049(2004).
RN [15]
RP FUNCTION, INDUCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION, AND
RP UBIQUITINATION.
RX PubMed=17724032; DOI=10.1074/jbc.m703857200;
RA Qi X., Pohl N.M., Loesch M., Hou S., Li R., Qin J.Z., Cuenda A., Chen G.;
RT "p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-
RT proteasome pathways in regulating Ras transformation and stress response.";
RL J. Biol. Chem. 282:31398-31408(2007).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF DLG1.
RX PubMed=20605917; DOI=10.1242/jcs.066514;
RA Sabio G., Cerezo-Guisado M.I., Del Reino P., Inesta-Vaquera F.A.,
RA Rousseau S., Arthur J.S., Campbell D.G., Centeno F., Cuenda A.;
RT "p38gamma regulates interaction of nuclear PSF and RNA with the tumour-
RT suppressor hDlg in response to osmotic shock.";
RL J. Cell Sci. 123:2596-2604(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP FUNCTION.
RX PubMed=21172807; DOI=10.1242/jcs.068254;
RA Kukkonen-Macchi A., Sicora O., Kaczynska K., Oetken-Lindholm C.,
RA Pouwels J., Laine L., Kallio M.J.;
RT "Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell
RT death.";
RL J. Cell Sci. 124:216-227(2011).
RN [19]
RP INVOLVEMENT IN CANCER.
RX PubMed=21532888; DOI=10.1593/neo.101748;
RA Meng F., Zhang H., Liu G., Kreike B., Chen W., Sethi S., Miller F.R.,
RA Wu G.;
RT "p38gamma mitogen-activated protein kinase contributes to oncogenic
RT properties maintenance and resistance to poly (ADP-ribose)-polymerase-1
RT inhibition in breast cancer.";
RL Neoplasia 13:472-482(2011).
RN [20]
RP REVIEW ON ACTIVITY REGULATION, AND REVIEW ON FUNCTION.
RX PubMed=20626350; DOI=10.1042/bj20100323;
RA Cuadrado A., Nebreda A.R.;
RT "Mechanisms and functions of p38 MAPK signalling.";
RL Biochem. J. 429:403-417(2010).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-185, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [22]
RP INTERACTION WITH PTPN4.
RX PubMed=27246854; DOI=10.1074/jbc.m115.707208;
RA Maisonneuve P., Caillet-Saguy C., Vaney M.C., Bibi-Zainab E., Sawyer K.,
RA Raynal B., Haouz A., Delepierre M., Lafon M., Cordier F., Wolff N.;
RT "Molecular Basis of the Interaction of the Human Protein Tyrosine
RT Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein
RT Kinase p38gamma.";
RL J. Biol. Chem. 291:16699-16708(2016).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS), COFACTOR, AND SUBUNIT.
RX PubMed=10508788; DOI=10.1016/s0969-2126(99)80173-7;
RA Bellon S., Fitzgibbon M.J., Fox T., Hsiao H.M., Wilson K.P.;
RT "The structure of phosphorylated p38gamma is monomeric and reveals a
RT conserved activation-loop conformation.";
RL Structure 7:1057-1065(1999).
RN [24]
RP VARIANTS [LARGE SCALE ANALYSIS] MET-103 AND ASN-230.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Serine/threonine kinase which acts as an essential component
CC of the MAP kinase signal transduction pathway. MAPK12 is one of the
CC four p38 MAPKs which play an important role in the cascades of cellular
CC responses evoked by extracellular stimuli such as pro-inflammatory
CC cytokines or physical stress leading to direct activation of
CC transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs
CC phosphorylate a broad range of proteins and it has been estimated that
CC they may have approximately 200 to 300 substrates each. Some of the
CC targets are downstream kinases such as MAPKAPK2, which are activated
CC through phosphorylation and further phosphorylate additional targets.
CC Plays a role in myoblast differentiation and also in the down-
CC regulation of cyclin D1 in response to hypoxia in adrenal cells
CC suggesting MAPK12 may inhibit cell proliferation while promoting
CC differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12
CC in the cell nucleus increases its association with nuclear DLG1,
CC thereby causing dissociation of DLG1-SFPQ complexes. This function is
CC independent of its catalytic activity and could affect mRNA processing
CC and/or gene transcription to aid cell adaptation to osmolarity changes
CC in the environment. Regulates UV-induced checkpoint signaling and
CC repair of UV-induced DNA damage and G2 arrest after gamma-radiation
CC exposure. MAPK12 is involved in the regulation of SLC2A1 expression and
CC basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4
CC expression and contraction-mediated glucose uptake in adult skeletal
CC muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and
CC inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is
CC required for the normal kinetochore localization of PLK1, prevents
CC chromosomal instability and supports mitotic cell viability. MAPK12-
CC signaling is also positively regulating the expansion of transient
CC amplifying myogenic precursor cells during muscle growth and
CC regeneration. {ECO:0000269|PubMed:10848581,
CC ECO:0000269|PubMed:14592936, ECO:0000269|PubMed:17724032,
CC ECO:0000269|PubMed:20605917, ECO:0000269|PubMed:21172807,
CC ECO:0000269|PubMed:8633070, ECO:0000269|PubMed:9430721}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.24;
CC Evidence={ECO:0000269|PubMed:10212242};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.24; Evidence={ECO:0000269|PubMed:10212242};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:10508788};
CC Note=Binds 2 magnesium ions. {ECO:0000269|PubMed:10508788};
CC -!- ACTIVITY REGULATION: Activated by phosphorylation on threonine and
CC tyrosine. MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the
CC activation of MAPK12 induced by environmental stress, whereas
CC MAP2K6/MKK6 is the major MAPK12 activator in response to TNF-alpha.
CC {ECO:0000269|PubMed:10212242, ECO:0000269|PubMed:9430721}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=37 uM for ATP {ECO:0000269|PubMed:10212242};
CC KM=313 uM for EGFR substrate peptide {ECO:0000269|PubMed:10212242};
CC KM=254 uM for GST-ATF2 {ECO:0000269|PubMed:10212242};
CC -!- SUBUNIT: Monomer. Interacts with the PDZ domain of the syntrophin
CC SNTA1. Interacts with SH3BP5. Interacts with LIN7C, SCRIB and SYNJ2BP
CC (By similarity). Interacts with PTPN4; this interaction induces the
CC activation of PTPN4 phosphatase activity. {ECO:0000250,
CC ECO:0000269|PubMed:27246854}.
CC -!- INTERACTION:
CC P53778; P05067: APP; NbExp=3; IntAct=EBI-602406, EBI-77613;
CC P53778; Q12959: DLG1; NbExp=2; IntAct=EBI-602406, EBI-357481;
CC P53778; Q16512: PKN1; NbExp=2; IntAct=EBI-602406, EBI-602382;
CC P53778; P29074: PTPN4; NbExp=2; IntAct=EBI-602406, EBI-710431;
CC P53778; Q14160: SCRIB; NbExp=6; IntAct=EBI-602406, EBI-357345;
CC P53778; Q8IUQ4: SIAH1; NbExp=3; IntAct=EBI-602406, EBI-747107;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Mitochondrion.
CC Note=Mitochondrial when associated with SH3BP5. In skeletal muscle
CC colocalizes with SNTA1 at the neuromuscular junction and throughout the
CC sarcolemma (By similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P53778-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P53778-2; Sequence=VSP_055224;
CC -!- TISSUE SPECIFICITY: Highly expressed in skeletal muscle and heart.
CC {ECO:0000269|PubMed:11991731, ECO:0000269|PubMed:8633070}.
CC -!- INDUCTION: Expression of MAPK12 is down-regulation by MAPK14
CC activation. {ECO:0000269|PubMed:17724032}.
CC -!- DOMAIN: The TXY motif contains the threonine and tyrosine residues
CC whose phosphorylation activates the MAP kinases.
CC -!- PTM: Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K3/MKK3 and
CC MAP2K6/MKK6, which activates the enzyme. {ECO:0000269|PubMed:11010976,
CC ECO:0000269|PubMed:17724032}.
CC -!- PTM: Ubiquitinated. Ubiquitination leads to degradation by the
CC proteasome pathway. {ECO:0000269|PubMed:17724032}.
CC -!- DISEASE: Note=MAPK is overexpressed in highly metastatic breast cancer
CC cell lines and its expression is preferentially associated with basal-
CC like and metastatic phenotypes of breast tumor samples.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. MAP kinase subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/MAPK12ID41290ch22q13.html";
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DR EMBL; X79483; CAA55984.1; -; mRNA.
DR EMBL; Y10487; CAA71511.1; -; mRNA.
DR EMBL; U66243; AAB40118.1; -; mRNA.
DR EMBL; CR456515; CAG30401.1; -; mRNA.
DR EMBL; AL022328; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC015741; AAH15741.1; -; mRNA.
DR CCDS; CCDS14089.1; -. [P53778-1]
DR CCDS; CCDS77688.1; -. [P53778-2]
DR PIR; JC5252; JC5252.
DR PIR; JC6138; JC6138.
DR RefSeq; NP_001290181.1; NM_001303252.2. [P53778-2]
DR RefSeq; NP_002960.2; NM_002969.5. [P53778-1]
DR PDB; 1CM8; X-ray; 2.40 A; A/B=1-367.
DR PDB; 4QUM; X-ray; 2.52 A; B=182-190.
DR PDB; 6UNA; X-ray; 2.55 A; A/B=7-367.
DR PDB; 7CGA; X-ray; 3.15 A; A/B/C/D=9-353.
DR PDBsum; 1CM8; -.
DR PDBsum; 4QUM; -.
DR PDBsum; 6UNA; -.
DR PDBsum; 7CGA; -.
DR AlphaFoldDB; P53778; -.
DR SMR; P53778; -.
DR BioGRID; 112207; 46.
DR CORUM; P53778; -.
DR DIP; DIP-34241N; -.
DR IntAct; P53778; 31.
DR MINT; P53778; -.
DR STRING; 9606.ENSP00000215659; -.
DR BindingDB; P53778; -.
DR ChEMBL; CHEMBL4674; -.
DR DrugBank; DB05403; CEP-1347.
DR DrugBank; DB05157; KC706.
DR DrugBank; DB01017; Minocycline.
DR DrugBank; DB04395; Phosphoaminophosphonic Acid-Adenylate Ester.
DR DrugBank; DB02482; Phosphonothreonine.
DR DrugCentral; P53778; -.
DR GuidetoPHARMACOLOGY; 1501; -.
DR iPTMnet; P53778; -.
DR PhosphoSitePlus; P53778; -.
DR BioMuta; MAPK12; -.
DR DMDM; 2851522; -.
DR CPTAC; CPTAC-874; -.
DR CPTAC; CPTAC-875; -.
DR EPD; P53778; -.
DR jPOST; P53778; -.
DR MassIVE; P53778; -.
DR MaxQB; P53778; -.
DR PaxDb; P53778; -.
DR PeptideAtlas; P53778; -.
DR PRIDE; P53778; -.
DR ProteomicsDB; 56615; -. [P53778-1]
DR Antibodypedia; 14291; 548 antibodies from 38 providers.
DR DNASU; 6300; -.
DR Ensembl; ENST00000215659.13; ENSP00000215659.8; ENSG00000188130.14. [P53778-1]
DR Ensembl; ENST00000622558.4; ENSP00000479972.1; ENSG00000188130.14. [P53778-2]
DR GeneID; 6300; -.
DR KEGG; hsa:6300; -.
DR MANE-Select; ENST00000215659.13; ENSP00000215659.8; NM_002969.6; NP_002960.2.
DR UCSC; uc003bkl.2; human. [P53778-1]
DR CTD; 6300; -.
DR DisGeNET; 6300; -.
DR GeneCards; MAPK12; -.
DR HGNC; HGNC:6874; MAPK12.
DR HPA; ENSG00000188130; Group enriched (skeletal muscle, tongue).
DR MIM; 602399; gene.
DR neXtProt; NX_P53778; -.
DR OpenTargets; ENSG00000188130; -.
DR PharmGKB; PA30619; -.
DR VEuPathDB; HostDB:ENSG00000188130; -.
DR eggNOG; KOG0660; Eukaryota.
DR GeneTree; ENSGT00940000156189; -.
DR InParanoid; P53778; -.
DR OMA; AEPMIRE; -.
DR OrthoDB; 233858at2759; -.
DR PhylomeDB; P53778; -.
DR TreeFam; TF105100; -.
DR BRENDA; 2.7.11.24; 2681.
DR PathwayCommons; P53778; -.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-171007; p38MAPK events.
DR Reactome; R-HSA-2151209; Activation of PPARGC1A (PGC-1alpha) by phosphorylation.
DR Reactome; R-HSA-376172; DSCAM interactions.
DR Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway.
DR Reactome; R-HSA-525793; Myogenesis.
DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
DR SignaLink; P53778; -.
DR SIGNOR; P53778; -.
DR BioGRID-ORCS; 6300; 5 hits in 1110 CRISPR screens.
DR ChiTaRS; MAPK12; human.
DR EvolutionaryTrace; P53778; -.
DR GeneWiki; MAPK12; -.
DR GenomeRNAi; 6300; -.
DR Pharos; P53778; Tchem.
DR PRO; PR:P53778; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; P53778; protein.
DR Bgee; ENSG00000188130; Expressed in gastrocnemius and 161 other tissues.
DR ExpressionAtlas; P53778; baseline and differential.
DR Genevisible; P53778; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0004707; F:MAP kinase activity; IBA:GO_Central.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; TAS:ProtInc.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
DR GO; GO:0007517; P:muscle organ development; TAS:ProtInc.
DR GO; GO:0045445; P:myoblast differentiation; IDA:UniProtKB.
DR GO; GO:0045786; P:negative regulation of cell cycle; IEA:Ensembl.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0051149; P:positive regulation of muscle cell differentiation; TAS:Reactome.
DR GO; GO:0010952; P:positive regulation of peptidase activity; NAS:ParkinsonsUK-UCL.
DR GO; GO:0051726; P:regulation of cell cycle; TAS:ProtInc.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd07880; STKc_p38gamma; 1.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR003527; MAP_kinase_CS.
DR InterPro; IPR008352; MAPK_p38-like.
DR InterPro; IPR038786; p38gamma.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR Pfam; PF00069; Pkinase; 1.
DR PRINTS; PR01773; P38MAPKINASE.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS01351; MAPK; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell cycle; Cytoplasm;
KW Kinase; Magnesium; Metal-binding; Mitochondrion; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Stress response; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1..367
FT /note="Mitogen-activated protein kinase 12"
FT /id="PRO_0000186282"
FT DOMAIN 27..311
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOTIF 183..185
FT /note="TXY"
FT ACT_SITE 153
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 33..41
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 56
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 183
FT /note="Phosphothreonine; by MAP2K3 and MAP2K6"
FT /evidence="ECO:0000250|UniProtKB:Q63538"
FT MOD_RES 185
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 142..151
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15461802"
FT /id="VSP_055224"
FT VARIANT 103
FT /note="T -> M (in dbSNP:rs34422484)"
FT /evidence="ECO:0000269|PubMed:15461802,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_042265"
FT VARIANT 230
FT /note="D -> N (in dbSNP:rs35396905)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042266"
FT VARIANT 244
FT /note="T -> M (in dbSNP:rs2066776)"
FT /id="VAR_012002"
FT MUTAGEN 179
FT /note="D->A: Emulation of the active state."
FT /evidence="ECO:0000269|PubMed:15284239"
FT MUTAGEN 185
FT /note="Y->F: Loss of activity."
FT /evidence="ECO:0000269|PubMed:8633070"
FT MUTAGEN 330
FT /note="F->S: No effect."
FT /evidence="ECO:0000269|PubMed:15284239"
FT CONFLICT 7
FT /note="A -> T (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 70
FT /note="R -> L (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 138
FT /note="L -> M (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 201..202
FT /note="MR -> IA (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 261
FT /note="Y -> N (in Ref. 3; AAB40118)"
FT /evidence="ECO:0000305"
FT CONFLICT 297..298
FT /note="EQ -> DI (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 300
FT /note="V -> L (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 305
FT /note="A -> F (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 307
FT /note="A -> S (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT CONFLICT 332..333
FT /note="DV -> YF (in Ref. 1; CAA55984)"
FT /evidence="ECO:0000305"
FT STRAND 11..15
FT /evidence="ECO:0007829|PDB:6UNA"
FT STRAND 17..21
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 24..32
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 41..46
FT /evidence="ECO:0007829|PDB:1CM8"
FT TURN 47..49
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 52..57
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 65..80
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 90..93
FT /evidence="ECO:0007829|PDB:1CM8"
FT TURN 99..101
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 106..110
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 116..122
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 127..146
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 156..158
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:1CM8"
FT STRAND 167..169
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 189..191
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 195..198
FT /evidence="ECO:0007829|PDB:1CM8"
FT TURN 199..201
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 207..221
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 231..242
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 247..251
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 256..264
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 273..275
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 282..291
FT /evidence="ECO:0007829|PDB:1CM8"
FT TURN 296..298
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 302..307
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:1CM8"
FT TURN 312..314
FT /evidence="ECO:0007829|PDB:1CM8"
FT HELIX 329..332
FT /evidence="ECO:0007829|PDB:6UNA"
FT HELIX 337..349
FT /evidence="ECO:0007829|PDB:1CM8"
SQ SEQUENCE 367 AA; 41940 MW; EF680401D8E40610 CRC64;
MSSPPPARSG FYRQEVTKTA WEVRAVYRDL QPVGSGAYGA VCSAVDGRTG AKVAIKKLYR
PFQSELFAKR AYRELRLLKH MRHENVIGLL DVFTPDETLD DFTDFYLVMP FMGTDLGKLM
KHEKLGEDRI QFLVYQMLKG LRYIHAAGII HRDLKPGNLA VNEDCELKIL DFGLARQADS
EMTGYVVTRW YRAPEVILNW MRYTQTVDIW SVGCIMAEMI TGKTLFKGSD HLDQLKEIMK
VTGTPPAEFV QRLQSDEAKN YMKGLPELEK KDFASILTNA SPLAVNLLEK MLVLDAEQRV
TAGEALAHPY FESLHDTEDE PQVQKYDDSF DDVDRTLDEW KRVTYKEVLS FKPPRQLGAR
VSKETPL
